Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 42
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361017

RESUMO

Glycogen synthase kinase-3 beta (GSK-3ß) is an enzyme pertinently linked to neurodegenerative diseases since it is associated with the regulation of key neuropathological features in the central nervous system. Among the different kinds of inhibitors of this kinase, the allosteric ones stand out due to their selective and subtle modulation, lowering the chance of producing side effects. The mechanism of GSK-3ß allosteric modulators may be considered still vague in terms of elucidating a well-defined binding pocket and a bioactive pose for them. In this context, we propose to reinvestigate and reinforce such knowledge by the application of an extensive set of in silico methodologies, such as cavity detection, ligand 3D shape analysis and docking (with robust validation of corresponding protocols), and molecular dynamics. The results here obtained were consensually consistent in furnishing new structural data, in particular by providing a solid bioactive pose of one of the most representative GSK-3ß allosteric modulators. We further applied this to the prospect for new compounds by ligand-based virtual screening and analyzed the potential of the two obtained virtual hits by quantum chemical calculations. All potential hits achieved will be subsequently tested by in vitro assays in order to validate our approaches as well as to unveil novel chemical entities as GSK-3ß allosteric modulators.


Assuntos
Sítio Alostérico , Glicogênio Sintase Quinase 3 beta/química , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/farmacologia , Regulação Alostérica , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Fármacos Neuroprotetores/química , Ligação Proteica
2.
J Biomol Struct Dyn ; : 1-23, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-33427075

RESUMO

Cyclooxygenase 2 (COX-2) is a well-established target for the design of anti-inflammatory intermediates. Celecoxib was selected as a template molecule to perform ligand-based virtual screening, i.e. to search for structures with similarity in shape and electrostatic potential, with a gradual increase in accuracy through the combined fitting of several steps using eight commercial databases. The molecules ZINC408709 and ZINC2090319 reproduced values within the limits established in an initial study of absorption and distribution in the body. No alert was fired for possible toxic groups when these molecules were subjected to toxicity prediction. Molecular docking results with these compounds showed a higher binding affinity in comparison to rofecoxib for the COX-2 target. Additionally, ZINC408709 and ZINC2090319 were predicted to be potentially biologically active. In in silico prediction of endocrine disruption potential, it was established that the molecule ZINC2090319 binds strongly to the target related to cardiovascular risk in a desirable way as a non-steroidal antagonist and ZINC408709 binds strongly to the target that is associated with the treatment of inflammatory pathologies and similar to celecoxib. Metabolites generated from these compounds are less likely to have side effects. Simulations were used to evaluate the interaction of compounds with COX-1 and COX-2 during 200 ns. Despite the differences, ZINC408709 molecule showed better stability for COX-2 during molecular dynamics simulation. In the calculations of free energy MM/PBSA, the molecule ZINC408709 ΔGbind value has a higher affinity to celecoxib and rofecoxib COX-2. This demonstrates that the selected substances can be considered as promising COX-2 inhibitors. Communicated by Ramaswamy H. Sarma.

3.
J Biomol Struct Dyn ; 39(9): 3115-3127, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32338151

RESUMO

Adenosine A2A receptor (A2AR) is the predominant receptor in immune cells, where its activation triggers cAMP-mediated immunosuppressive signaling and the underlying inhibition of T cells activation and T cells-induced effects mediated by cAMP-dependent kinase proteins mechanisms. In this study, were used ADME/Tox, molecular docking and molecular dynamics simulations to investigate selective adenosine A2AR agonists as potential anti-inflammatory drugs. As a result, we obtained two promising compounds (A and B) that have satisfactory pharmacokinetic and toxicological properties and were able to interact with important residues of the A2AR binding cavity and during the molecular dynamics simulations were able to keep the enzyme complexed.Communicated by Ramaswamy H. Sarma.

4.
Molecules ; 25(5)2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32164183

RESUMO

Adenosine Receptor Type 2A (A2AAR) plays a role in important processes, such as anti-inflammatory ones. In this way, the present work aimed to search for compounds by pharmacophore-based virtual screening. The pharmacokinetic/toxicological profiles of the compounds, as well as a robust QSAR, predicted the binding modes via molecular docking. Finally, we used molecular dynamics to investigate the stability of interactions from ligand-A2AAR. For the search for A2AAR agonists, the UK-432097 and a set of 20 compounds available in the BindingDB database were studied. These compounds were used to generate pharmacophore models. Molecular properties were used for construction of the QSAR model by multiple linear regression for the prediction of biological activity. The best pharmacophore model was used by searching for commercial compounds in databases and the resulting compounds from the pharmacophore-based virtual screening were applied to the QSAR. Two compounds had promising activity due to their satisfactory pharmacokinetic/toxicological profiles and predictions via QSAR (Diverset 10002403 pEC50 = 7.54407; ZINC04257548 pEC50 = 7.38310). Moreover, they had satisfactory docking and molecular dynamics results compared to those obtained for Regadenoson (Lexiscan®), used as the positive control. These compounds can be used in biological assays (in vitro and in vivo) in order to confirm the potential activity agonist to A2AAR.


Assuntos
Receptores A2 de Adenosina/metabolismo , Adenosina/análogos & derivados , Adenosina/farmacologia , Agonistas do Receptor A2 de Adenosina/farmacologia , Humanos , Ligantes , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade
5.
Cent Nerv Syst Agents Med Chem ; 20(2): 128-143, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32065095

RESUMO

BACKGROUND: Drugs used for Parkinson's disease (PD) are mainly responsible for only relieving major symptoms, but may present several side effects that are typical of such pharmacological treatment. METHODS: This study aimed to use in silico methods for drug designing inhibitors of the PD therapeutic target, monoamine oxidase B (MAO-B). Thus, 20 MAO-B inhibitors from the BindingDB database were selected followed by a calculation of their descriptors at DFT B3LYP/6-31G** level of theory. RESULTS: Statistical analysis considering a Pearson correlation matrix led to the selection of electrophilicity index as a descriptor related to the biological activity of inhibitors. Furthermore, based on the prediction of suitable ADME/Tox properties, the molecule CID 54583085 was selected as a template to carry out structural modifications to obtain 3 analogues, whereas molecules B and C showed significant improvement in mutagenicity and carcinogenicity, in relation to the template. CONCLUSION: Thus, it is concluded that the proposed modifications led us to satisfactory results, since there was an improvement in the toxicological properties of molecules, however, further studies must be carried out to evaluate their biological activities as possible MAO-B inhibitors for PD treatment.

6.
Mini Rev Med Chem ; 20(9): 754-767, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31686637

RESUMO

Parkinson's Disease (PD) is the second most common neurodegenerative disease in the elderly population, with a higher prevalence in men, independent of race and social class; it affects approximately 1.5 to 2.0% of the elderly population over 60 years and 4% for those over 80 years of age. PD is caused by the necrosis of dopaminergic neurons in the substantia nigra, which is the brain region responsible for the synthesis of the neurotransmitter dopamine (DA), resulting in its decrease in the synaptic cleft. The monoamine oxidase B (MAO-B) degrades dopamine, promoting the glutamate accumulation and oxidative stress with the release of free radicals, causing excitotoxicity. The PD symptoms are progressive physical limitations such as rigidity, bradykinesia, tremor, postural instability and disability in functional performance. Considering that there are no laboratory tests, biomarkers or imaging studies to confirm the disease, the diagnosis of PD is made by analyzing the motor features. There is no cure for PD, and the pharmacological treatment consists of a dopaminergic supplement with levodopa, COMT inhibitors, anticholinergics agents, dopaminergic agonists, and inhibitors of MAO-B, which basically aims to control the symptoms, enabling better functional mobility and increasing life expectancy of the treated PD patients. Due to the importance and increasing prevalence of PD in the world, this study reviews information on the pathophysiology, symptomatology as well as the most current and relevant treatments of PD patients.


Assuntos
Dopaminérgicos/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Antagonistas Colinérgicos/uso terapêutico , Agonistas de Dopamina/uso terapêutico , Humanos , Levodopa/uso terapêutico , Expectativa de Vida , Inibidores da Monoaminoxidase/uso terapêutico , Estresse Oxidativo , Doença de Parkinson/diagnóstico
7.
Molecules ; 24(16)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31416180

RESUMO

Leukemias are neoplasms that affect hematopoietic cells, which are developed by genetic alterations (mutations) that lead to the loss of proliferation control mechanisms (maturation and/or cell death). The α4ß1 integrin receptor is a therapeutic target for inflammation, autoimmune diseases and lymphoid tumors. This study was carried out to search through the antagonists-based virtual screening for α4ß1 receptor. Initially, seventeen (17) structures were selected (based on the inhibitory activity values, IC50) and the structure with the best value was chosen as the pivot. The pharmacophoric pattern was determined from the online PharmaGist server and resulted in a model of score value equal to 97.940 with 15 pharmacophoric characteristics that were statistically evaluated via Pearson correlations, principal component analysis (PCA) and hierarchical clustering analysis (HCA). A refined model generated four pharmacophoric hypotheses totaling 1.478 structures set of Zinc_database. After, the pharmacokinetic, toxicological and biological activity predictions were realized comparing with pivot structure that resulted in five (ZINC72088291, ZINC68842860, ZINC14365931, ZINC09588345 and ZINC91247798) structures with optimal in silico predictions. Therefore, future studies are needed to confirm antitumor potential activity of molecules selected this work with in vitro and in vivo assays.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Simulação por Computador , Ensaios de Seleção de Medicamentos Antitumorais , Peptídeos/química , Peptídeos/farmacologia , Análise por Conglomerados , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Humanos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Relação Estrutura-Atividade
8.
Molecules ; 24(1)2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30609687

RESUMO

A drug design for safer phenylbutazone was been explored by reactivity and docking studies involving single electron transfer mechanism, as well as toxicological predictions. Several approaches about its structural properties were performed through quantum chemistry calculations at the B3LYP level of theory, together with the 6-31+G(d,p) basis sets. Molecular orbital and ionization potential were associated to electron donation capacity. The spin densities contribution showed a preferential hydroxylation at the para-positions of phenyl ring when compared to other positions. In addition, on electron abstractions the aromatic hydroxylation has more impact than alkyl hydroxylation. Docking studies indicate that six structures 1, 7, 8 and 13⁻15 have potential for inhibiting human as well as murine COX-2, due to regions showing similar intermolecular interactions to the observed for the control compounds (indomethacin and refecoxib). Toxicity can be related to aromatic hydroxylation. In accordance to our calculations, the derivatives here proposed are potentially more active as well safer than phenylbutazone and only structures 8 and 13⁻15 were the most promising. Such results can explain the biological properties of phenylbutazone and support the design of potentially safer candidates.


Assuntos
Fenilbutazona/química , Fenilbutazona/farmacologia , Descoberta de Drogas/métodos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Fenilbutazona/efeitos adversos , Fenilbutazona/toxicidade , Relação Estrutura-Atividade
9.
J Mol Model ; 24(9): 225, 2018 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-30088101

RESUMO

Receptor-interacting protein kinase 2 (RIPK2) plays an essential role in autoimmune response and is suggested as a target for inflammatory diseases. A pharmacophore model was built from a dataset with ponatinib (template) and 18 RIPK2 inhibitors selected from BindingDB database. The pharmacophore model validation was performed by multiple linear regression (MLR). The statistical quality of the model was evaluated by the correlation coefficient (R), squared correlation coefficient (R2), explanatory variance (adjusted R2), standard error of estimate (SEE), and variance ratio (F). The best pharmacophore model has one aromatic group (LEU24 residue interaction) and two hydrogen bonding acceptor groups (MET98 and TYR97 residues interaction), having a score of 24.739 with 14 aligned inhibitors, which were used in virtual screening via ZincPharmer server and the ZINC database (selected in function of the RMSD value). We determined theoretical values of biological activity (logRA) by MLR, pharmacokinetic and toxicology properties, and made molecular docking studies comparing binding affinity (kcal/mol) results with the most active compound of the study (ponatinib) and WEHI-345. Nine compounds from the ZINC database show satisfactory results, yielding among those selected, the compound ZINC01540228, as the most promising RIPK2 inhibitor. After binding free energy calculations, the following molecular dynamics simulations showed that the receptor protein's backbone remained stable after the introduction of ligands.


Assuntos
Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteína Serina-Treonina Quinase 2 de Interação com Receptor , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Inflamação/patologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/antagonistas & inibidores , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/química , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo
10.
Molecules ; 23(2)2018 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-29463017

RESUMO

The Protein Kinase Receptor type 2 (RIPK2) plays an important role in the pathogenesis of inflammatory diseases; it signals downstream of the NOD1 and NOD2 intracellular sensors and promotes a productive inflammatory response. However, excessive NOD2 signaling has been associated with various diseases, including sarcoidosis and inflammatory arthritis; the pharmacological inhibition of RIPK2 is an affinity strategy that demonstrates an increased expression of pro-inflammatory secretion activity. In this study, a pharmacophoric model based on the crystallographic pose of ponatinib, a potent RIPK2 inhibitor, and 30 other ones selected from the BindingDB repository database, was built. Compounds were selected based on the available ZINC compounds database and in silico predictions of their pharmacokinetic, toxicity and potential biological activity. Molecular docking was performed to identify the probable interactions of the compounds as well as their binding affinity with RIPK2. The compounds were analyzed to ponatinib and WEHI-345, which also used as a control. At least one of the compounds exhibited suitable pharmacokinetic properties, low toxicity and an interesting binding affinity and high fitness compared with the crystallographic pose of WEHI-345 in complex with RIPK2. This compound also possessed suitable synthetic accessibility, rendering it a potential and very promising RIPK2 inhibitor to be further investigated in regards to different diseases, particularly inflammatory ones.


Assuntos
Imidazóis/química , Inflamação/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Piridazinas/química , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/antagonistas & inibidores , Cristalografia por Raios X , Humanos , Imidazóis/uso terapêutico , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas/uso terapêutico , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/química , Transdução de Sinais/efeitos dos fármacos , Interface Usuário-Computador
11.
J Biomol Struct Dyn ; 36(2): 318-334, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28027711

RESUMO

Human dipeptidyl peptidase IV (hDDP-IV) has a considerable importance in inactivation of glucagon-like peptide-1, which is related to type 2 diabetes. One approach for the treatment is the development of small hDDP-IV inhibitors. In order to design better inhibitors, we analyzed 5-(aminomethyl)-6-(2,4-dichlrophenyl)-2-(3,5-dimethoxyphenyl)pyrimidin-4-amine and a set of 24 molecules found in the BindingDB web database for model designing. The analysis of their molecular properties allowed the design of a multiple linear regression model for activity prediction. Their docking analysis allowed visualization of the interactions between the pharmacophore regions and hDDP-IV. After both analyses were performed, we proposed a set of nine molecules in order to predict their activity. Four of them displayed promising activity, and thus, had their docking performed, as well as, the pharmacokinetic and toxicological study. Two compounds from the proposed set showed suitable pharmacokinetic and toxicological characteristics, and therefore, they were considered promising for future synthesis and in vitro studies.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/química , Hipoglicemiantes/química , Sítios de Ligação , Dipeptidil Peptidase 4/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/química , Humanos , Hipoglicemiantes/uso terapêutico , Modelos Moleculares , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
12.
ChemMedChem ; 12(16): 1408-1416, 2017 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-28417566

RESUMO

Cannabis sativa withdrawal syndrome is characterized mainly by psychological symptoms. By using computational tools, the aim of this study was to propose drug candidates for treating withdrawal syndrome based on the natural ligands of the cannabinoid type 1 receptor (CB1). One compound in particular, 2-n-butyl-5-n-pentylbenzene-1,3-diol (ZINC1730183, also known as stemphol), showed positive predictions as a human CB1 ligand and for facile synthetic accessibility. Therefore, ZINC1730183 is a favorable candidate scaffold for further research into pharmacotherapeutic alternatives to treat C. sativa withdrawal syndrome.


Assuntos
Cannabis/química , Ligantes , Receptor CB1 de Canabinoide/metabolismo , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Células CACO-2 , Cannabis/metabolismo , Permeabilidade da Membrana Celular/efeitos dos fármacos , Desenho de Fármacos , Meia-Vida , Humanos , Camundongos , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/metabolismo , Resorcinóis/química , Resorcinóis/farmacocinética , Resorcinóis/farmacologia , Resorcinóis/uso terapêutico , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/patologia
13.
Arthritis Res Ther ; 19(1): 47, 2017 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-28270195

RESUMO

BACKGROUND: The inhibition of pyrimidine biosynthesis by blocking the dihydroorotate dehydrogenase (DHODH) activity, the prime target of leflunomide (LEF), has been proven to be an effective strategy for rheumatoid arthritis (RA) treatment. However, a considerable proportion of RA patients are refractory to LEF. Here, we investigated lapachol (LAP), a natural naphthoquinone, as a potential DHODH inhibitor and addressed its immunosuppressive properties. METHODS: Molecular flexible docking studies and bioactivity assays were performed to determine the ability of LAP to interact and inhibit DHODH. In vitro studies were conducted to assess the antiproliferative effect of LAP using isolated lymphocytes. Finally, collagen-induced arthritis (CIA) and antigen-induced arthritis (AIA) models were employed to address the anti-arthritic effects of LAP. RESULTS: We found that LAP is a potent DHODH inhibitor which had a remarkable ability to inhibit both human and murine lymphocyte proliferation in vitro. Importantly, uridine supplementation abrogated the antiproliferative effect of LAP, supporting that the pyrimidine metabolic pathway is the target of LAP. In vivo, LAP treatment markedly reduced CIA and AIA progression as evidenced by the reduction in clinical score, articular tissue damage, and inflammation. CONCLUSIONS: Our findings propose a binding model of interaction and support the ability of LAP to inhibit DHODH, decreasing lymphocyte proliferation and attenuating the severity of experimental autoimmune arthritis. Therefore, LAP could be considered as a potential immunosuppressive lead candidate with potential therapeutic implications for RA.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Imunossupressores/farmacologia , Naftoquinonas/farmacologia , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Simulação de Acoplamento Molecular , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Ratos , Ratos Wistar
14.
Eur J Pharmacol ; 783: 11-22, 2016 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-27118175

RESUMO

Diabetes mellitus is associated with reactive oxygen and nitrogen species accumulation. Behavioral stress increases nitric oxide production, which may trigger a massive impact on vascular cells and accelerate cardiovascular complications under oxidative stress conditions such as Diabetes. For this study, type-1 Diabetes mellitus was induced in Wistar rats by intraperitoneal injection of streptozotocin. After 28 days, cumulative concentration-response curves for angiotensin II were obtained in endothelium-intact carotid rings from diabetic rats that underwent to acute restraint stress for 3h. The contractile response evoked by angiotensin II was increased in carotid arteries from diabetic rats. Acute restraint stress did not alter angiotensin II-induced contraction in carotid arteries from normoglycaemic rats. However acute stress combined with Diabetes increased angiotensin II-induced contraction in carotid rings. Western blot experiments and the inhibition of nitric oxide synthases in functional assays showed that neuronal, endothelial and inducible nitric oxide synthase isoforms contribute to the increased formation of peroxynitrite and contractile hyperreactivity to angiotensin II in carotid rings from stressed diabetic rats. In summary, these findings suggest that the increased superoxide anion generation in carotid arteries from diabetic rats associated to the increased local nitric oxide synthases expression and activity induced by acute restrain stress were responsible for exacerbating the local formation of peroxynitrite and the contraction induced by angiotensin II.


Assuntos
Angiotensina II/farmacologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico/biossíntese , Ácido Peroxinitroso/biossíntese , Estresse Psicológico/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/fisiopatologia , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Experimental/psicologia , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 1/psicologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Ativação Enzimática/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Masculino , Óxido Nítrico Sintase/química , Fenilefrina/farmacologia , Fosforilação/efeitos dos fármacos , Ratos , Ratos Wistar , Restrição Física , Vasoconstrição/efeitos dos fármacos
15.
Eur J Pharmacol ; 769: 143-6, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26548625

RESUMO

The interplay between angiotensin AT1 receptors and MAS receptors relies on several inward regulatory mechanisms from renin-angiotensin system (RAS) including the functional crosstalk between angiotensin II and angiotensin-(1-7), the competitive AT1 antagonism exhibited by angiotensin-(1-7), the antagonist feature assigned to AT1/MAS heterodimerization on AT1 signaling and the AT1-mediated downregulation of angiotensin-converting enzyme 2 (ACE2). Recently, such interplay has acquired an important significance to RAS Pharmacology since a few studies have supporting strong evidences that MAS receptors mediate the effects elicited by AT1 antagonists. The present Perspective provides an overview of the regulatory mechanisms involving AT1 and MAS receptors, their significance to RAS Pharmacology and the future directions on the interplay between angiotensin receptors.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Proteínas Proto-Oncogênicas/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Humanos
16.
Eur J Pharmacol ; 765: 503-16, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26387612

RESUMO

Hyperglycemia increases the generation of reactive oxygen species and affects systems that regulate the vascular tone including renin-angiotensin system. Stress could exacerbate intracellular oxidative stress during Diabetes upon the activation of angiotensin AT1/NADPH oxidase pathway, which contributes to the development of diabetic cardiovascular complications. For this study, type-I Diabetes was induced in Wistar rats by intraperitoneal injection of streptozotocin. 28 days after streptozotocin injection, the animals underwent to acute restraint stress for 3 h. Cumulative concentration-response curves for angiotensin II were obtained in carotid rings pre-treated or not with Nox or cyclooxygenase inhibitors. Nox1 or Nox4 expression and activity were assessed by Western blotting and lucigenin chemiluminescence, respectively. The role of Nox1 and Nox4 on reactive oxygen species generation was evaluated by flow cytometry and Amplex Red assays. Cyclooxygenases expression was assessed by real-time polymerase chain reaction. The contractile response evoked by angiotensin II was increased in diabetic rat carotid. Acute restraint stress increased this response in this vessel by mechanisms mediated by Nox4, whose local expression and activity in generating hydrogen peroxide are increased. The contractile hyperreactivity to angiotensin II in stressed diabetic rat carotid is also mediated by metabolites derived from cyclooxygenase-2, whose local expression is increased. Taken together, our findings suggest that acute restraint stress exacerbates the contractile hyperreactivity to angiotensin II in diabetic rat carotid by enhancing Nox4-driven generation of hydrogen peroxide, which evokes contractile tone by cyclooxygenases-dependent mechanisms. Finally, these findings highlight the harmful role played by acute stress in modulating diabetic vascular complications.


Assuntos
Artérias Carótidas/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , NADPH Oxidases/fisiologia , Estresse Psicológico/metabolismo , Acetilcolina/farmacologia , Angiotensina II/farmacologia , Animais , Artérias Carótidas/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , NADPH Oxidase 4 , Técnicas de Cultura de Órgãos , Ratos , Ratos Wistar , Restrição Física/efeitos adversos , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologia
17.
Eur J Pharmacol ; 764: 173-188, 2015 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-26144375

RESUMO

AT1 antagonists effectively prevent atherosclerosis since AT1 upregulation and angiotensin II-induced proinflammatory actions are critical to atherogenesis. Despite the classic mechanisms underlying the vasoprotective and atheroprotective actions of AT1 antagonists, the cross-talk between angiotensin-converting enzyme-angiotensin II-AT1 and angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axes suggests other mechanisms beyond AT1 blockage in such effects. For instance, angiotensin-converting enzyme 2 activity is inhibited by reactive oxygen species derived from AT1-mediated proinflammatory signaling. Since angiotensin-(1-7) promotes antiatherogenic effects, we hypothesized that the vasoprotective and atheroprotective effects of AT1 antagonists could result from their inhibitory effects on the AT1-mediated negative modulation of vascular angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis functionality. Interestingly, our results showed that early atherosclerosis triggered in thoracic aorta from high cholesterol fed-Apolipoprotein E-deficient mice impairs angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis functionality by a proinflammatory-redox AT1-mediated pathway. In such mechanism, AT1 activation leads to the aortic release of tumor necrosis factor-α, which stimulates NAD(P)H oxidase/Nox1-driven generation of superoxide and hydrogen peroxide. While hydrogen peroxide inhibits angiotensin-converting enzyme 2 activity, superoxide impairs MAS functionality. Candesartan treatment restored the functionality of angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis by inhibiting the proinflammatory-redox AT1-mediated mechanism. Candesartan also promoted vasoprotective and atheroprotective effects that were mediated by MAS since A779 (MAS antagonist) co-treatment inhibited them. The role of MAS receptors as the final mediators of the vasoprotective and atheroprotective effects of candesartan was supported by the vascular actions of angiotensin-(1-7) upon the recovery of the functionality of vascular angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Angiotensina I/metabolismo , Benzimidazóis/farmacologia , Cardiotônicos/farmacologia , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Tetrazóis/farmacologia , Enzima de Conversão de Angiotensina 2 , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Apolipoproteínas E/genética , Aterosclerose/sangue , Aterosclerose/patologia , Colesterol/sangue , Citocinas/genética , Citocinas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADH NADPH Oxirredutases/metabolismo , NADPH Oxidase 1 , Receptor Tipo 1 de Angiotensina/metabolismo , Triglicerídeos/sangue , Molécula 1 de Adesão de Célula Vascular/genética
18.
Eur J Pharmacol ; 764: 118-123, 2015 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-26142084

RESUMO

The important role played by aryl hydrocarbon receptor activation in the pathophysiology of atherosclerosis induced by cigarette smoke exposure has spurred the clinical interest in the development of aryl hydrocarbon receptor antagonists with atheroprotective efficacy. A few aryl hydrocarbon receptor antagonists were developed but the lack of structural information regarding the receptor ligand binding domain resulted in several limitations in the pharmacological properties of these compounds including partial agonism, allosterism, non-selectivity, cytotoxicity and susceptibility to bioactivation. These limitations make the progress of preclinical and clinical assays with the available aryl hydrocarbon receptor antagonists difficult. There is a great interest in developing pure, competitive, selective, nontoxic and resistant to bioactivation aryl hydrocarbon receptor antagonists. Current technology permits the development of pharmacologically ideal antagonists based on the chemical features of the aryl hydrocarbon receptor ligand binding domain. According to these characteristics, chlorinated derivatives of trans-stilbene meta-substituted with electrophilic aromatic directing groups would be effective prototypes for pure, competitive, selective, nontoxic and resistant to bioactivation antagonists for such receptor.


Assuntos
Aterosclerose/tratamento farmacológico , Descoberta de Drogas/métodos , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Animais , Aterosclerose/metabolismo , Humanos , Receptores de Hidrocarboneto Arílico/química , Receptores de Hidrocarboneto Arílico/metabolismo
19.
Mini Rev Med Chem ; 13(9): 1348-56, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23544601

RESUMO

Many plants are used in traditional medicine as active agents against various effects of snake bites. Phospholipase A2 enzymes are commonly found in venoms of snakes of the Viperidae and Elaphidae families, which are their main components. This article presents an overview of inhibitors isolated from plants, which show antiophidian properties.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Fosfolipases A2/efeitos dos fármacos , Plantas Medicinais , Mordeduras de Serpentes , Humanos
20.
Biotechnol Lett ; 34(8): 1487-92, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22481300

RESUMO

Eugenitin, a chromone derivative and a metabolite of the endophyte Mycoleptodiscus indicus, at 5 mM activated a recombinant GH11 endo-xylanase by 40 %. The in silico prediction of ligand-binding sites on the three-dimensional structure of the endo-xylanase revealed that eugenitin interacts mainly by a hydrogen bond with a serine residue and a stacking interaction of the heterocyclic aromatic ring system with a tryptophan residue. Eugenitin improved the GH11 endo-xylanase activity on different substrates, modified the optimal pH and temperature activities and slightly affected the kinetic parameters of the enzyme.


Assuntos
Ascomicetos/química , Cromonas/farmacologia , Endo-1,4-beta-Xilanases/metabolismo , Aspergillus/enzimologia , Aspergillus/genética , Aspergillus/metabolismo , Cromonas/química , Cromonas/metabolismo , Dimetil Sulfóxido , Endo-1,4-beta-Xilanases/química , Endófitos/química , Ativação Enzimática , Estabilidade Enzimática , Concentração de Íons de Hidrogênio , Hidrólise , Cinética , Modelos Moleculares , Software , Temperatura
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...